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Structure‐based JAZ ligand‐J1 and its analogues show strong cytotoxic effects on glioma cells in vitro ‐ A new class of glioma therapy drugs?
Author(s) -
Qiu Jingxin,
Yang Mingli,
May W. Stratford,
Ostrov David A.,
Keith Robertson D.,
Harrison Jeffrey K.,
Yachnis Anthony T.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.706.19
Subject(s) - glioma , cytotoxic t cell , cancer research , in vivo , in vitro , carcinogenesis , biology , apoptosis , flow cytometry , chemistry , microbiology and biotechnology , biochemistry , gene , genetics
Hypoxia/ischemia and oxidative stress has been shown to be involved in glioma tumorigenesis. The Jaz gene encodes a zinc finger protein that can respond to oxidative stress with increased expression both in vitro and in vivo . We have previously reported that JAZ exhibits a tumor grade‐dependent increased expression in gliomas with the highest levels in GBM and shows increased cytoplasm‐nuclear translocation adjacent to pseudopalisading necrosis. We hypothesized that JAZ plays a role in glioma tumorigenesis. Targeting JAZ with a molecular docking approach, we identified one small molecule compound named “J1” that exhibited strong dose‐ and time‐dependent glioma cytotoxic effects in vitro (human U87MG, U118MG, A172, and mouse GL261 glioma cell lines) with GI50 around 25microM. Several known J1 analogues also displayed differential glioma killing effects. Flow cytometry showed that J1 led to cell cycle arrest. Quantitative proteomic analysis revealed that, in both U87MG and U118MG glioma cells, J1 treatment led to a significant decrease of PLOD2 (procollagen hydroxylase 2), which is known to be induced by hypoxia, associated with cancer progression, and was reported to be increased in pseudopalisading GBM cells. These results suggest that JAZ ligand J1 and its analogues have the potential to become a new class of chemotherapy drugs for glioma treatment.